Hematology. American Society of Hematology. Education Program最新文献

Allogeneic hematopoietic stem cell transplantation (allo-HCT) remains a cornerstone in the treatment of high-risk acute lymphoblastic leukemia (ALL), yet optimal patient selection is challenging in the era of rapidly changing modern therapy. Refined molecular characterization allows for better risk assessment, sparing low-risk patients from allo-HCT toxicity while identifying those who may benefit from intensified approaches. Measurable residual disease (MRD) has emerged as a powerful predictor of relapse irrespective of treatment strategy, challenging the necessity of transplant in MRD-negative patients. Further, expanded donor options, particularly haploidentical transplantation coupled with reduced intensity conditioning, have extended the applicability of allo-HCT to a broader range of patients. Finally, immunotherapies and targeted treatments are increasingly integrated into both initial and relapsed treatment protocols yielding deep remission and allowing for successful transplant in patients with a history of advanced disease. In this review, we provide an overview of the contemporary role of transplant in adult patients with ALL, focusing on indications for allo-HCT in first remission, optimal sequencing of transplant with novel therapies, and advancements in donor selection and conditioning regimens.

Hydroxyurea has historically been the sole disease-modifying medication (DMM) for sickle cell disease (SCD). However, 3 newer DMMs, L-glutamine, voxelotor, and crizanlizumab, were approved for children and adolescents with SCD since 2017. Despite their emergence, treatment barriers, including access, affordability, and nonadherence, limit the optimization of DMMs in the clinical setting. Furthermore, there is limited work outlining real-world use and safety of the newer DMMs, and no published guidelines advise how best to select between DMMs or to use multiple in combination. Meanwhile, each DMM is associated with unique characteristics, such as tolerability, cost, and route of administration, which must be considered when weighing these options with patients and families. This article discusses DMMs for SCD and offers practical guidance on using the available DMMs in real-world settings based on published peer-reviewed studies and considering patient preferences. The recent withdrawal of one of these DMMs (voxelotor) from the market highlights the need for additional DMMs and evidence-based practices for adding DMMs and when to progress towards curative therapies.

Heavy menstrual bleeding (HMB) is a common problem, presenting in 1 in 5 females. The quantification of menstrual blood loss and the subsequent treatment of HMB are both nuanced tasks that require the physician to consider the patient perspective. The individualization of care and transition to methods that fit each individual patient are critical to building a successful relationship with the patient to facilitate follow-up care and evaluation of response to treatment. In this review we outline various methods of quantification of menstrual blood loss, including considerations of accuracy and practicality. These methods, all of which have the potential for clinical benefit, vary from pictorial assessment charts to the gold standard alkaline hematin method to asking the patient about their average amount of blood loss and how it affects their quality of life. Next, we outline nonsurgical treatments for HMB, including hormonal and nonhormonal options, and consider the potential for success, as well as treatment considerations and contraindications. Overall, options for the evaluation and nonsurgical management of menstrual blood loss and HMB are presented along with quality-of-life considerations.

Treatment for relapsed/refractory (R/R) follicular lymphoma (FL) has evolved over recent years with the introduction of multiple novel immunotherapies: anti-CD3  ×  CD20 bispecific antibody (BsAb) T-cell engagers and anti-CD19 chimeric antigen receptor T cells (CAR T). Both drug classes are highly active, and their adverse event profiles overlap considerably, with cytokine release syndrome, cytopenias, and infections being most common. However, key differences include accessibility and logistical considerations as well as distinct neurologic toxicities, which make recommending a BsAb or CAR T a nuanced decision for each patient with R/R FL. Notably, patients could receive both classes of therapies in sequence; however, data guiding this decision are sparse. Considering the 3 most advanced agents in each class, we generally favor BsAbs before CAR T as the standard-of-care third-line treatment for the typical patient with R/R FL without concern for aggressive histologic transformation (HT). This is based on a 3-year follow-up of the mosunetuzumab phase 2 trial in R/R FL highlighting durable complete responses after a time-limited therapy with an acceptable safety profile for patients of all ages and reasonable performance status. We generally prioritize CAR T before BsAbs for patients with proven or suspected HT given the curative-potential of this approach based on trial data from R/R diffuse large B-cell lymphoma; it is unknown whether BsAbs offer the same long-term benefit in transformed FL. Overall, with the ability to personalize the sequencing of BsAbs and CAR T, the recently expanding portfolio of highly effective immunotherapies for R/R FL is poised to offer considerable benefit to this patient population.

The term hemochromatosis refers to a group of genetic disorders characterized by hepcidin insufficiency in the context of normal erythropoiesis, iron hyperabsorption, and expansion of the plasma iron pool with increased transferrin saturation, the diagnostic hallmark of the disease. This results in the formation of toxic non-transferrin-bound iron, which ultimately accumulates in multiple organs, including the liver, heart, endocrine glands, and joints. The most common form is HFE-hemochromatosis (HFE-H) due to p.Cys282Tyr (C282Y) homozygosity, present in nearly 1 in 200 people of Northern European descent but characterized by low penetrance, particularly in females. Genetic and lifestyle cofactors (especially alcohol and dysmetabolic features) significantly modulate clinical expression so that HFE-H can be considered a multifactorial disease. Nowadays, HFE-H is mostly diagnosed before organ damage and is easily treated by phlebotomy, with an excellent prognosis. After iron depletion, maintenance phlebotomy can be usefully transformed into a blood donation program. Lifestyle changes are important for management. Non-HFE-H, much rarer but highly penetrant, may lead to early and severe heart, liver, and endocrine complications. Managing severe hemochromatosis requires a comprehensive approach optimally provided by consultation with specialized centers. In clinical practice, a proper diagnostic approach is paramount for patients referred for hyperferritinemia, a frequent finding that reflects hemochromatosis only in a minority of cases.

The treatment paradigm for classic Hodgkin lymphoma (CHL) continues to evolve, particularly in light of the incorporation of programmed cell death protein 1 (PD-1) inhibitors into a variety of therapeutic settings. PD-1 inhibitors have demonstrated high efficacy and a favorable toxicity profile when added to a doxorubicin, vinblastine, dacarbazine chemotherapy backbone in patients with untreated CHL. PD-1 inhibitors are also effective treatment options in the relapsed/refractory setting. For patients who are pursuing autologous stem cell transplant (ASCT), pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin has shown marked efficacy and is an effective treatment regimen to administer prior to transplant. For patients who either are not eligible for ASCT or have relapsed after ASCT, pembrolizumab or nivolumab monotherapy have been well studied and demonstrate high efficacy even when patients have been exposed to numerous lines of prior therapy. As data from previous trials continue to mature and new clinical trials are conducted, PD-1 inhibitors will continue to become an integral component for successful management of CHL.

Patients with β-thalassemia continue to have several unmet needs. In non-transfusion-dependent patients, untreated ineffective erythropoiesis and anemia have been associated with a variety of clinical sequelae, with no treatment currently available beyond supportive transfusions. In transfusion-dependent forms, lifelong transfusion and iron chelation therapy are associated with considerable clinical, psychological, and economic burden on the patient and health care system. Luspatercept is a novel disease-modifying agent targeting ineffective erythropoiesis that became recently available for patients with β-thalassemia. Data from randomized clinical trials confirmed its efficacy and safety in reducing transfusion burden in transfusion-dependent patients and increasing total hemoglobin level in non-transfusion-dependent patients. Secondary clinical benefits in patient-reported outcomes and iron overload were also observed on long-term therapy, and further data from real-world evidence studies are awaited.

The mortality burden of sickle cell anemia (SCA) is centered in sub-Saharan Africa. In addition to a lack of systematic programs for early diagnosis, access to disease-modifying treatments is limited to only a few urban centers. Providing a safe and adequate blood supply is a major challenge, heightening mortality from SCA-associated complications that require urgent blood transfusion and making the delivery of regular transfusion therapy for stroke prevention nonfeasible. Hydroxyurea therapy with proven clinical benefits for pain episodes, acute chest syndrome, malaria, transfusions, hospitalizations, and stroke prevention is the most feasible treatment for SCA in Africa. Access barriers to hydroxyurea treatment include poor availability, unaffordable costs, health professionals' reluctance to prescribe, a lack of national guidelines, and exaggerated fears about drug toxicities. Strategies for the local manufacture of hydroxyurea combined with the systematic education and training of health professionals using guidelines supported by the World Health Organization can help surmount the access barriers. Hematopoietic stem cell transplantation as a curative therapy is available in only 7 countries in Africa. The few patients who have suitable sibling donors and can afford a transplant must usually travel out of the country for treatment, returning to their home countries where expertise and resources for posttransplant follow-up are lacking. The recently developed ex-vivo gene therapies are heavily dependent on technical infrastructure to deliver, a daunting challenge for Africa. Future in-vivo gene therapies that bypass myeloablation and ex-vivo processing would be more suitable. However, enthusiasm for pursuing these gene therapies should not overlook strategies to make hydroxyurea universally accessible in Africa.

Thrombocytopenia is a frequent complication in patients with cancer, mostly due to the myelosuppressive effects of antineoplastic therapies. The risk of venous thromboembolism (VTE) in patients with cancer is increased despite low platelet counts. The management of cancer-associated VTE in patients with thrombocytopenia is challenging, as the risk of both recurrent VTE and bleeding complications is high. Moreover, the time-dependent nature of thrombocytopenia over the course of antineoplastic therapies further complicates the management of patients in clinical practice. In the absence of evidence from high-quality studies, the management of anticoagulation therapy for VTE must be personalized, balancing the individual risk of VTE progression and recurrence against the risk of hemorrhage. In the present case-based review, we highlight the clinical challenges that arise upon managing cancer-associated VTE in the setting of present or anticipated thrombocytopenia, summarize the available evidence, and provide a comparative overview of available guidelines.

The term heparin resistance is likely best defined as the failure of an appropriate dose of unfractionated heparin (UFH) to achieve a predetermined level of anticoagulation. Unfortunately, and despite many prior reports, there is no established consensus as to what either the appropriate dose or the predetermined level should be. Traditionally, assays used to monitor anticoagulation with UFH have been clot based, including the activated partial thromboplastin time, used for patients on the ward or intensive care unit, and the activated clotting time, used for patients undergoing vascular interventions and cardiopulmonary bypass. Unfortunately, these tests may be highly influenced by other factors occurring in many patients, especially those with inflammation or acute infection, as noted during the COVID-19 pandemic. Many hospitals have thus moved to anti-Xa testing for heparin monitoring. Another important factor in defining heparin resistance includes dosing, whether weight-based or total daily dosing is used, as initial reports of heparin resistance described daily doses independent of body weight. Multiple causes of apparent heparin resistance include hypercoagulability, antithrombin deficiency, andexanet alfa used for direct oral anticoagulant reversal, thrombocytosis, and antiphospholipid antibody syndromes. Treatment options for managing patients with heparin resistance include weight-based dosing and administration of additional UFH, antithrombin supplementation, or the use of an alternative anticoagulant such as the direct thrombin inhibitors bivalirudin or argatroban.